The long-range goals of the principal investigator are to examine mechanisms that regulate the circulation in humans. The specific goals of this program are to better understand the mechanisms regulating coronary blood flow during exercise. A key feature of this proposal is that we will use duplex ultrasound to measure coronary blood flow in the left anterior descending coronary artery. The specific aims of this application are: We will demonstrate that coronary constriction (i.e. a rise in coronary vascular resistance) occurs during handgrip. We will also determine the mechanism for this constriction. We hypothesize that constriction will occur at high percentages of maximal voluntary contraction (MVC). We hypothesize that this effect will be due predominantly to engagement of the muscle mechanoreflex. We will also determine if coronary vasoconstrictor responses to handgrip are enhanced with aging and heart failure (HF). We hypothesize that this will be the case and that this accentuated effect will be due to heightened activation of muscle mechanoreflexes in the aged and HF. We will then examine the efferent mechanisms that regulate coronary constrictor responses in humans. We hypothesize that constrictor mechanisms will be blocked by the intravenous use of a 1-blocker (phentolamine), accentuated in the presence of acute intravenous 2-blocker (propranolol), and in the presence of hyperoxia (an intervention to increase the oxidative quenching of nitric oxide). Over the past 5 to 6 years we have worked hard to develop the duplex method to examine renal blood flow velocity. This has resulted in a series of papers that have defined the role of muscle mechanoreceptors in generating sympathetic constriction to the kidney in normal humans, the aged and in HF. Recently we have focused attention on the regulation of blood flow in coronary arteries of conscious humans. We began this effort by invasively measuring coronary blood flow using an intracardiac Doppler wire; we then performed studies measuring flow velocity in left internal mammary artery bypass grafts in subjects with surgically treated coronary artery disease. Most recently we have gathered pilot data examining coronary flow in native coronary arteries. This method has taken several years to develop. We are now poised to utilize this method to address the mechanisms that control blood flow to the left anterior descending artery in normal volunteers, in those with HF, and in the aged. Understanding the mechanisms that control blood flow during exercise is an important area of study as blood flow to the heart is a crucial determinant of a person's ability to perform the activities of daily living. Greater understanding of the nervous system's ability to regulate the coronary circulation will afford us the opportunity to develop novel ways of treating conditions where coronary regulation is impaired such as HF. PUBLIC HEALTH RELEVANCE: We will examine coronary blood flow non-invasively during exercise. Understanding the mechanisms that control blood flow during exercise is an important area of study as blood flow to the heart is an important determinant of a person's ability to perform the activities of daily living. Greater understanding of the nervous system's ability to regulate the coronary circulation will afford us the opportunity to develop novel ways of treating conditions where coronary regulation is impaired such as HF. [unreadable] [unreadable] [unreadable] [unreadable]